title: IGF-1 receptor antagonism inhibits autophagy.
abstract: Inhibition of the insulin/insulin-like growth factor signalling pathway increases lifespan and protects against neurodegeneration in model organisms, and has been considered as a potential therapeutic target. This pathway is upstream of mTORC1, a negative regulator of autophagy. Thus, we expected autophagy to be activated by insulin-like growth factor-1 (IGF-1) inhibition, which could account for many of its beneficial effects. Paradoxically, we found that IGF-1 inhibition attenuates autophagosome formation. The reduced amount of autophagosomes present in IGF-1R depleted cells can be, at least in part, explained by a reduced formation of autophagosomal precursors at the plasma membrane. In particular, IGF-1R depletion inhibits mTORC2, which, in turn, reduces the activity of protein kinase C (PKCα/β). This perturbs the actin cytoskeleton dynamics and decreases the rate of clathrin-dependent endocytosis, which impacts autophagosome precursor formation. Finally, with important implications for human diseases, we demonstrate that pharmacological inhibition of the IGF-1R signalling cascade reduces autophagy also in zebrafish and mice models. The novel link we describe here has important consequences for the interpretation of genetic experiments in mammalian systems and for evaluating the potential of targeting the IGF-1R receptor or modulating its signalling through the downstream pathway for therapeutic purposes under clinically relevant conditions, such as neurodegenerative diseases, where autophagy stimulation is considered beneficial.
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Renna
authors.forename: Carla F
authors.initials: CF
authors.lastname: Bento
authors.forename: Angeleen
authors.initials: A
authors.lastname: Fleming
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Menzies
authors.forename: Farah H
authors.initials: FH
authors.lastname: Siddiqi
authors.forename: Brinda
authors.initials: B
authors.lastname: Ravikumar
authors.forename: Claudia
authors.initials: C
authors.lastname: Puri
authors.forename: Moises
authors.initials: M
authors.lastname: Garcia-Arencibia
authors.forename: Oana
authors.initials: O
authors.lastname: Sadiq
authors.forename: Silvia
authors.initials: S
authors.lastname: Corrochano
authors.forename: Sarah
authors.initials: S
authors.lastname: Carter
authors.forename: Steve D M
authors.initials: SD
authors.lastname: Brown
authors.forename: Abraham
authors.initials: A
authors.lastname: Acevedo-Arozena
authors.forename: David C
authors.initials: DC
authors.lastname: Rubinsztein
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000473:pathology; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D018942:Macrolides; D046912:Multiprotein Complexes; C057620:bafilomycin A; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D011493:Protein Kinase C